Adriamycin (doxorubicin) and the related anthracycline antibiotics are potent, broad-spectrum, antineoplastic agents, but their therapeutic usefulness is limited by severe cardiotoxicity. The proposed research will test the hypothesis that adriamycin interacts with cardiolipin (diphosphatidylglycerol), a unique mitonchondrial phospholipid, inducing peroxidation of the lipid and interfering with one or more cardiolipin-dependent processes, so as ultimately to disrupt cellular homeostasis. Complementary studies of unilamellar liposomes and isolated rat heart mitochondria will be used to address four specific aims: (1) Identification of the mitochondrial process(es) mediated by cardiolipin and determination of their sensitivity to adriamycin. Experiments will focus on Ca2+ transport, phosphate (Pi) transport, and electron transport mediated by defined regions of the respiratory chain. (2) Estimation of the effect of lipid, particularly cardiolipin, peroxidation on cardiolipin function in the liposome model and on development in vitro and in vivo of adriamycin effects on mitochondria. (3) Identification of the factor(s) that render cardiac tissue especially susceptible to the toxic effects of the anthracyclines. Heart and liver will be compared in terms of the extent of cardiolipin peroxidation induced by adriamycin and the magnitude and adriamycin-sensitivity of cardiolipin-mediated processes. (4) Comparison of the effects on cardiolipin function and cardiolipin peroxidation of adriamycin analogs differing in cardiotoxicity. The overall goal is a sufficiently detailed description of the biochemistry of adriamycin cardiotoxicity to permit the design of efficacious protective strategies. However, a broadened understanding of the Ca2+ transport mechanisms of heart mitochondria would also contribute to the successful management of conditions, such as ischemia, prolonged hypoxia, and some cardiomyopathies, in which cardiac damage results from failure of intracellular Ca2+ homeostasis.
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